U.S. patent application number 09/811494 was filed with the patent office on 2001-08-23 for chewable tablets containing mannitol and aspartame.
This patent application is currently assigned to Advanced Technology Pharmaceuticals Corporation. Invention is credited to Valentine, William, Valentine, William K..
Application Number | 20010016208 09/811494 |
Document ID | / |
Family ID | 22722914 |
Filed Date | 2001-08-23 |
United States Patent
Application |
20010016208 |
Kind Code |
A1 |
Valentine, William ; et
al. |
August 23, 2001 |
Chewable tablets containing mannitol and Aspartame
Abstract
Chewable tablets and particulate food and pharmaceutical
products are disclosed which are made from agglomerates comprising
an alcohol sugar such as mannitol and a high intensity sweetener
such as Aspartame from which agglomerate tablets may be directly
compressed, and processes for making the agglomerates and tablets.
The tablets or particulate product containing the agglomerate may
contain active ingredients blended with the agglomerate or as part
of the agglomerate structure. Tablets and particulate products
according to the invention can contain active ingredients such as
pharmaceuticals (e.g., antacids, analgesics, cough medicine, drugs,
etc.) breath sweeteners, vitamins and dietary supplements, to name
a few. The high intensity sweetener containing agglomerates can
also be used to make solid food mix type products such as sugar
free ice tea mixes.
Inventors: |
Valentine, William;
(Lawrenceville, GA) ; Valentine, William K.;
(Lawrenceville, GA) |
Correspondence
Address: |
DELIO & PETERSON
121 WHITNEY AVENUE
NEW HAVEN
CT
06510
|
Assignee: |
Advanced Technology Pharmaceuticals
Corporation
|
Family ID: |
22722914 |
Appl. No.: |
09/811494 |
Filed: |
March 19, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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09811494 |
Mar 19, 2001 |
|
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09195811 |
Nov 19, 1998 |
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Current U.S.
Class: |
424/465 ;
514/21.91 |
Current CPC
Class: |
A23V 2002/00 20130101;
A23V 2250/2482 20130101; A23V 2250/6418 20130101; A23G 3/42
20130101; A61K 9/0056 20130101; A23G 3/38 20130101; A61K 9/2013
20130101; A61K 9/2018 20130101; A23V 2002/00 20130101 |
Class at
Publication: |
424/465 ;
514/19 |
International
Class: |
A61K 009/20 |
Claims
Thus, having described the invention, what is claimed is:
1. A chewable tablet containing a high intensity sweetener
comprising a compressed agglomerate, the agglomerate comprising an
alcohol sugar, a high intensity sweetener and a water-soluble
binder.
2. The tablet according to claim 1 wherein the tablet contains an
active ingredient.
3. The tablet according to claim 1 wherein the agglomerate
comprises, by weight, about 80% to about 97% of an alcohol sugar,
about 1% to 10% high intensity sweetener and up to about 10%
binder.
4. The tablet according to claim 1 wherein the hardness is about
3-8 kp.
5. The tablet of claim 1 wherein the binder is an alcohol
sugar.
6. The tablet according to claim 1 wherein the alcohol sugar is
selected from the group consisting of mannitol, sorbitol and
xylitol.
7. The tablet according to claim 6 wherein the alcohol sugar is
mannitol.
8. The tablet according to claim 6 wherein the high intensity
sweetener is selected from the group consisting of dipeptides,
Acesulfame, Alatame, Steviasides, saccharin and cyclamate.
9. The tablet according to claim 8 wherein the high intensity
sweetener is the dipeptide Aspartame.
10. The tablet according to claim 9 wherein the alcohol sugar is
mannitol.
11. The tablet according to claim 1 containing an effervescing
agent.
12. The tablet according to claim 11 wherein the effervescing agent
is a bicarbonate.
13. A tablet containing a high intensity sweetener comprising a
compressed agglomerate, the agglomerate comprising an alcohol
sugar, a water-soluble binder, a high intensity sweetener and an
active ingredient.
14. The tablet according to claim 13 wherein the alcohol sugar is
selected from the group consisting of mannitol, sorbitol and
xylitol.
15. The tablet according to claim 14 wherein the alcohol sugar is
mannitol.
16. The tablet according to claim 13 wherein the high intensity
sweetener is selected from the group consisting of dipeptides,
Acesulfame, Alatame, Steviasides, saccharin and cyclamates.
17. The tablet according to claim 16 wherein the high intensity
sweetener is the dipeptide Aspartame and the alcohol sugar is
mannitol.
18. The tablet according to claim 13 wherein the active ingredient
is a pharmaceutical.
19. The tablet according to claim 17 wherein the active ingredient
is a pharmaceutical.
20. The tablet according to claim 13 containing an effervescing
agent.
21. An agglomerate high intensity sweetener composition comprising
an alcohol sugar and a high intensity sweetener.
22. The agglomerate sweetener composition of claim 21 wherein the
agglomerate contains a water-soluble binder.
23. The agglomerate sweetener composition of claim 22 wherein the
high intensity sweetener is selected from the group of dipeptides,
Acesulfame, Alatame, Steviasides, saccharin and cyclamate.
24. The agglomerate sweetener composition of claim 23 wherein the
alcohol sugar is mannitol and the high intensity sweetener is
Aspartame.
25. The agglomerate sweetener composition of claim 21 wherein the
alcohol sugar is formed into an agglomerate and the high intensity
sweetener is sorbed on to the agglomerate.
26. The agglomerate sweetener composition of claim 21 wherein the
alcohol sugar and the high intensity sweetener are formed into an
agglomerate using a fluidized bed process.
27. The agglomerate sweetener composition of claim 26 wherein a
binder is used to form the agglomerate.
28. The agglomerate sweetener composition of claim 27 wherein the
binder is maltodextrin or the alcohol sugar.
29. The agglomerate sweetener composition of claim 24 wherein a
binder is used to form the agglomerate using a fluidized bed
process.
30. The agglomerate sweetener composition of claim 29 wherein the
binder is maltodextrin or mannitol.
31. The agglomerate sweetener composition of claim 27 wherein the
binder solution contains a high intensity sweetener.
32. The agglomerate sweetener composition of claim 31 wherein the
alcohol sugar is mannitol and the high intensity sweetener is
Aspartame.
33. The agglomerate sweetener composition of claim 21 wherein the
agglomerate contains an active ingredient.
34. The agglomerate sweetener composition of claim 33 wherein the
agglomerate is formed using a fluid bed process.
35. The agglomerate sweetener composition of claim 34 wherein the
active ingredient is in the fluid bed.
36. A chewable tablet made according to a process which comprises:
a. forming an agglomerate comprising an alcohol sugar, a high
intensity sweetener and a binder, said agglomerate being formed
using a fluid bed process and having a porous structure; b. mixing
the agglomerate of step (a) with an active ingredient; and c.
directly compressing the mixture of step (b) into the tablet, the
compressed agglomerate forming a mechanically stable tablet having
an interior and an outer surface made from the agglomerate, the
outer surface being harder than the interior of the tablet, the
tablet having a hardness and the particle size of the alcohol
sugar, of the binder material and of the active ingredient being
such as to provide a tablet which is rapidly liquefiable into a
smooth liquid without perceivable grit when the tablet is
masticated and the tablet is contacted with saliva.
37. The tablet according to claim 36 wherein the agglomerate is
directly compressed in the presence of a lubricant.
38. The tablet according to claim 36 wherein the alcohol sugar is
selected from the group consisting of mannitol, sorbitol and
xybitol.
39. The tablet according to claim 38 wherein the alcohol sugar is
mannitol.
40. The tablet according to claim 39 wherein the high intensity
sweetener is selected from the group consisting of dipeptides,
Acesulfame, Alatame, Steviasides, saccharin and cyclamate.
41. The tablet according to claim 40 wherein the high intensity
sweetener is the dipeptide Aspartame.
42. The tablet according to claim 41 wherein the binder is
maltodextrin or mannitol.
43. A chewable tablet made according to a process which comprises:
a. forming an agglomerate comprising an alcohol sugar, a high
intensity sweetener, a binder and an active ingredient said
agglomerate being formed using a fluid bed process; and b. directly
compressing the agglomerate into the tablet, the compressed
agglomerate forming a mechanically stable tablet having an interior
and an outer surface made from the agglomerate, the outer surface
being harder than the interior of the tablet, the tablet hardness
and the particle size of the alcohol sugar particles, of the binder
material and of the active ingredient being such as to provide a
tablet which is rapidly liquefiable into a smooth liquid without
perceivable grit when the tablet is masticated and the tablet is
contacted with saliva.
44. The tablet according to claim 43 wherein the agglomerate is
directly compressed in the presence of a lubricant.
45. The tablet according to claim 43 wherein the binder is an
alcohol sugar.
46. The tablet according to claim 45 wherein the alcohol sugar is
mannitol.
47. The tablet according to claim 44 wherein the high intensity
sweetener is selected from the group consisting of dipeptides,
Acesulfame, Alatame, Steriosides, saccharin and cyclamates.
48. The tablet according to claim 47 wherein the high intensity
sweetener is the dipeptide Aspartame.
49. The tablet according to claim 48 wherein the alcohol sugar is
mannitol.
50. A process for making an alcohol sugar agglomerate containing a
high intensity sweetener comprising the steps of forming a
fluidized bed of the alcohol sugar particles and high intensity
sweetener and spraying an aqueous solution of binder into the
fluidized bed, until a quantity of binder solution has been sprayed
into the fluidized bed such that the alcohol sugar, high intensity
sweetener, and the binder form the agglomerate which comprises, by
weight of the agglomerate, about 80% to about 97% alcohol sugar
particles, 1% to 10% high intensity sweetener and about 1% to about
10% binder, the agglomerate being capable of being compressed into
a mechanically stable tablet having an interior and an outer
surface formed from the agglomerate which outer surface is harder
than the interior of the tablet, the particle size of the alcohol
sugar particles and of the binder material from which the
agglomerate is made being such that the mechanically stable tablet
capable of being formed therefrom is rapidly liquefiable into a
smooth liquid without perceivable grit when the tablet is
masticated and the tablet is contacted with saliva.
51. The process according to claim 50 wherein the high intensity
sweetener is in the binder solution.
52. The process according to claim 50 wherein the fluidized bed
also includes an active ingredient.
53. The process according to claim 52 wherein the active ingredient
is in the binder solution.
54. The process according to claim 50 wherein the alcohol sugar is
mannitol and the high intensity sweetener is Aspartame.
55. A process for producing a chewable tablet comprising the steps
of: a. making an alcohol sugar agglomerate by a process comprising
forming a fluidized bed of alcohol sugar particles and a high
intensity sweetener, spraying an aqueous solution of binder into
the fluidized bed, the binder solution comprising a binder selected
from the group consisting of water-soluble carbohydrates, alcohol
sugar, maltodextrin, polyvinylpyrrolidone and carboxy methyl
cellulose, continuing the spraying until a quantity of binder
solution has been sprayed into the fluidized bed such that the
alcohol sugar particles, high intensity sweetener and the binder
form the resulting agglomerate which comprises by weight from about
80% to about 97% alcohol sugar particles, 1% to 10% high intensity
sweetener and about 1% to about 10% binder; b. mixing the
agglomerate of step a and an active ingredient; and c. compressing
the mixture of step b to form a mechanically stable tablet having
an interior and an outer surface made from the agglomerate, the
tablet at the outer surface being harder than in the interior, the
tablet hardness and the particle size of the alcohol sugar
particles, of the binder material and of the active ingredient
being such as to provide a tablet which is rapidly liquefiable into
a smooth liquid without perceivable grit when the tablet is
masticated and the tablet is contacted with saliva.
56. The process according to claim 55 wherein the agglomerate is
compressed in the presence of a lubricant.
57. The process according to claim 56 wherein high intensity
sweetener is in the binder solution.
58. The process according to claim 56 wherein the active ingredient
is in the binder solution.
59. The process according to claim 56 wherein the agglomerate is
compressed to a tablet hardness of from about 3 kp to about 8
kp.
60. A process for producing a chewable tablet comprising the steps
of: a. making a water-soluble alcohol sugar agglomerate comprising
forming a fluidized bed of alcohol sugar particles, high intensity
sweetener and an active ingredient, spraying an aqueous solution of
a binder into the fluidized bed, the binder solution comprising a
binder selected from the group consisting of maltodextrin, alcohol
sugar, polyvinylpyrrolidone and carboxy methyl cellulose, until the
agglomerate is formed; and b. compressing the agglomerate of step a
to form a mechanically stable tablet having an interior and an
outer surface made from the agglomerate, the tablet at the outer
surface being harder than in the interior, the tablet hardness and
the particle size of the alcohol sugar particles, of the binder
material and of the active ingredient being such as to provide a
tablet which is rapidly liquefiable into a smooth liquid without
perceivable grit when the tablet is masticated and the tablet is
contacted with saliva.
61. The process according to claim 60 wherein the agglomerate is
compressed in the presence of a lubricant.
62. The process according to claim 60 wherein the high intensity
sweetener is in the binder solution.
63. The process according to claim 60 wherein the active ingredient
is in the binder solution.
64. The process according to claim 61 wherein the agglomerate is
compressed to a tablet hardness of from about 3 kp to about 8 kp.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates generally to alcohol sugar
high intensity sweetener agglomerate compositions which are useful
in food and pharmaceutical products because of their flowability,
compressibility, mixability, stability and dissolution
characteristics, among others and, in particular, to agglomerates
of an alcohol sugar preferably mannitol and a high intensity
sweetener preferably Aspartame which agglomerates are made using a
fluid bed process and are used to make chewable tablets and
particulate products requiring a high intensity sweetener, and to
processes for making the co-agglomerates, tablets and particulate
products.
[0003] 2. Description of Related Art
[0004] A need has long existed in the food and pharmaceutical
industry for high intensity sweetener containing products in a
solid form which store well, are convenient and pleasant to take,
efficacious, fast acting and storage stable. For example, a
particulate product such as a sugar free ice tea mix requires that
the product be free flowing and the high intensity sweetener stable
to ingredients in the mix such as acidulents like citric acid. A
high intensity sweetener is also used for a masking purpose to mask
the bad taste of active ingredients in a product such as a chewable
tablet containing acetaminophen. Additionally, solid swallowable
antacid tablets are not particularly good tasting and do not
sweeten the breath, which would be extremely desirable
characteristics of a chewable tablet product for those who suffer
from esophagal reflux or sour breath.
[0005] High intensity sweeteners such as Aspartame unfortunately
are not easily formulated in food and pharmaceutical products and
this presents a formidable problem in the food and drug industries.
Aspartame, for example, contains groups such as dipeptide linkages
which are unstable when mixed with acidulents such as citric acid
or an alkaline antacid material such as magnesium hydroxide. The
breaking of the dipeptide link results in a loss of sweetness.
Aspartame also enters into Maillard type "browning" reactions when
mixed with a reducing sugar such as dextrose. Dissolution of the
high intensity sweetener is also a problem because they generally
evidence slow and undesirable dissolution in water, e.g., the
sweetener floats on the surface of the water and slowly dissolves
or the sweetener sinks to the bottom of the water and slowly
dissolves. High intensity sweeteners typically are commercially
available as fine powders which have a high degree of discernible
static charge which makes homogenous mixing of the formulation
difficult. Poor compressibility of high intensity sweeteners is an
additional problem for formulators.
[0006] Bearing in mind the problems and deficiencies of the prior
art, it is therefore an object of the present invention to provide
a high intensity sweetener agglomerate composition which is stable,
free flowing, compressible, mixable and has rapid dissolution
properties and which is capable of being used in a variety of solid
food and pharmaceutical products such as food and drink mixes and
chewable tablets.
[0007] It is another object of the present invention to provide a
tablet containing a high intensity sweetener which stores well and
liquefies quickly in the mouth upon chewing and is pleasant
tasting.
[0008] It is another object of the present invention to provide a
tablet containing a high intensity sweetener which is made by
direct compression and which tablet includes a substantial quantity
of the sweetener which in its raw material form is a powder that
can not be easily compacted into a cohesive tablet.
[0009] It is a further object of the invention to provide process
for making high intensity sweetener containing agglomerates which
can be used to make particulate and tablet food and pharmaceutical
products.
[0010] Other objects and advantages of the invention will be
readily apparent from the following description.
SUMMARY OF THE INVENTION
[0011] The above and other objects and advantages, which will be
apparent to those skilled in the art, are achieved in the present
invention which is directed to, in a broad aspect, an agglomerate
sweetener composition comprising an alcohol sugar such as mannitol
and a high intensity sweetener. The agglomerate typically has a
porous, high surface area void-like structure and is preferably
made using a fluidized bed process. The agglomerates preferably
comprise mannitol as the alcohol sugar and Aspartame as the high
intensity sweetener. A water soluble binder is used to form the
agglomerate and is selected from the group consisting of an alcohol
sugar which can be the same as the alcohol sugar forming the base
of the composition, a water soluble carbohydrate, maltodextrin,
polyvinylpyrrolidone and carboxy methyl cellulose (CMC) among
others. The preferred binders are the same alcohol sugar forming
the base and maltodextrin.
[0012] The quantity of water-soluble binder is an effective amount
needed to form the agglomerate and is in the range of up to about
10 percent by weight of the agglomerate (including the high
intensity sweetener), and preferably from about 1 percent to about
5 percent. The alcohol sugar particles comprise about 80 percent to
about 97 percent and the high intensity sweetener about 1 percent
to 10 percent by weight of the agglomerate (including the high
intensity sweetener). The ranges vary depending on the product in
which the agglomerate is to be used. The particle size of the
materials used to make the agglomerates and the particulate size of
the agglomerates may likewise vary widely as described below.
[0013] A tablet made according to the present invention is directly
compressed from the high surface area porous alcohol sugar based
high intensity sweetener agglomerate particles preferably using a
relatively low tabletting pressure to form a relatively soft,
quick-liquefying interior and a relatively hard, protective outer
shell which resists liquefaction even though it is formed from the
same agglomerate particles which form the tablet interior. At least
some of the ingredients of the agglomerate particles in the
interior of the tablet quickly dissolve or partially dissolve when
the tablet is broken into pieces and contacted with small amounts
of a liquid, particularly water and/or saliva, as during
mastication for example, and any remaining ingredients which do not
dissolve in the liquid become dispersed in the liquid and dissolved
ingredients, so that the resulting liquid is smooth and essentially
without perceivable grit. The relatively hard outer shell resists
liquefaction until it is broken, for example, by chewing.
Accordingly, the overall preferred chewable tablet structure is
such that the tablet is storage stable and easily portable, thereby
providing a unit dose in a most convenient form, but is also
readily liquefied and melts in the saliva of the mouth during
mastication without requiring water or some other liquid, so that
the tablet provides all of the benefits normally associated only
with liquid dosage forms.
[0014] Quick-liquifying, chewable tablets are shown in U.S. Pat.
No. 4,684,534, which patent is incorporated herein by reference and
which patent is assigned to the assignee of the present invention.
The patent discloses carbohydrate-based agglomerates, a method for
making the agglomerates and tablets made from the agglomerate.
[0015] The storage stable high intensity sweetener containing
agglomerate comprises an alcohol sugar, high intensity sweetener
and a water-soluble binder. The agglomerate may be used in food
products without an active ingredient. Typically the agglomerate is
used with an active ingredient such as in an ice tea mix or an
antacid tablet. The agglomerate is preferably blended with an
active ingredient in the formulation. The active ingredient and
agglomerate can also be mixed together to cause the active
ingredient to be entrained by and dispersed in the agglomerate.
This agglomerate can then be added to the product formulation. The
active ingredient can also be formed as part of the agglomerate
during the agglomeration process. The high intensity sweetener can
be sorbed onto a water-soluble agglomerate but this method and
agglomerate composition are not preferred.
[0016] The agglomerate as formed has a bulk density which is
relatively low compared to the alcohol sugar base and high
intensity sweetener which are used to make the agglomerate and is
typically in the range of about 0.35 gm/cc to about 0.55 gm/cc. A
substantial part of the agglomerate consists of voids, i.e., pores
or ducts, which provide an extremely large surface area capable of
entraining and dispersing substantial quantities of active
ingredients ordinarily about 10 percent to about 50 percent by
weight of the finished agglomerate (which includes the entrained
active ingredient). The agglomerate has particular utility as a
direct compression agglomerate from which tablets according to the
invention can be made particularly chewable tablets which liquify
in saliva.
[0017] A preferred process for making the alcohol sugar and high
intensity sweetener agglomerate comprises the steps of forming a
fluidized bed of the alcohol sugar and high intensity sweetener
particles, intermittently spraying a solution of the water soluble
binder in a droplet size into the fluidized bed so as to cause
intimate commingling of solution, alcohol sugar and high intensity
sweetener particles and adhesion together of alcohol sugar
particles and high intensity sweetener particles to form
agglomerated particles, drying the particles in the fluidized bed
between intermittent sprayings, and continuing spraying and drying
until the desired amount of binder solution has been sprayed into
the bed. Thereafter, the agglomerated particles are dried to a
desired moisture content or the equilibrium moisture content. The
amount of liquid binder solution sprayed corresponds to a binder
content in the agglomerate of from about 1 percent to about 10
percent by weight to the agglomerate. The alcohol sugar and high
intensity sweetener agglomerate and active ingredient and other
ingredients such as lubricants, flavors, etc. are mixed, preferably
in a low shear blender, to form a blend for tabletting by direct
compression or for use as a flowable food or pharmaceutical
product.
[0018] The agglomerate composition can also be made using a
granulating procedure whereby the alcohol sugar, high intensity
sweetener and binder are mixed together to form a paste like
material, screened, dried and sized.
[0019] The agglomerate can, as formed, be used to entrain the
active ingredient and other materials such as a lubricant and
flavors in the formulation to be made into a product. In addition,
an agglomerate containing the active ingredient as part of the
agglomerate structure can be formed by the process described above
for the agglomerate formed without an active ingredient, except
that the active ingredient is mixed with the alcohol sugar and high
intensity sweetener particles and a fluidized bed is formed of this
mixture. The active ingredient and/or high intensity sweetener may
also be added with the binder. Agglomerates formed with an active
ingredient have a porous structure similar to that of agglomerates
formed without an active ingredient.
[0020] The preferred method to form the agglomerate is by a
fluidized bed process wherein the alcohol sugar and high intensity
sweetener are fluidized and a binder solution sprayed onto the
fluidized bed.
[0021] It is preferred that the alcohol sugar particles used to
make the agglomerate pass about 50 mesh (particle size less than
about 300 microns). The high intensity sweetener typically passes
about 300 mesh (particle size less than about 50 microns). Mesh
sizes given therein refer to the U.S. Standard Sieve Series. The
final particle size of the agglomerate is preferably greater than
about 80 mesh (111 microns).
[0022] A process for making a tablet from the alcohol sugar-high
intensity sweetener agglomerates described above, typically
including about 0.4 percent to about 1 percent of a lubricant,
comprises compressing the agglomerate particles which were mixed
with any active ingredient, flavors, etc., in a conventional
tablet-forming apparatus to a hardness sufficient to hold the
tablet together and preferably substantially destroy the open pore
structure of the agglomerate at the surface of the tablet while
substantially maintaining the open pore, i.e., large surface area,
structure of the agglomerate in the interior of the tablet. Thus,
the agglomerate is compressed so that the interior of the tablet
preferably retains the essential porous structure and other
physical characteristics of the agglomerate which enable it to
liquify quickly, while the physical characteristics of the
agglomerate are changed primarily at the surface of the tablet.
[0023] For the materials described herein, it has been found that
the tablets are preferably compressed to a hardness generally about
3 kp to about 8 kp or higher, preferably about 6 kp, which
compression forms an interior which essentially retains the
physical structure of the agglomerate. A thinner outer shell is
preferred since more force is required to break a tablet with a
thicker shell and less material is provided in the interior of a
tablet having a thicker shell. Since the thickness of the outer
shell has been found to increase with tablet hardness, a preferred
range for compression of the agglomerate is a hardness of about 3
kp to about 6 kp.
[0024] Pressures applied to compress the agglomerates into tablets
having a hardness of about 3 kp to 6 kp were found to be in the
order of about one-third the pressures ordinarily used to make
tablets.
[0025] The term "high intensity sweetener" is used herein in a
broad sense and encompasses any high intensity sweetener material
which can be formed into an agglomerate or entrained in an
agglomerate. The preferred high intensity sweetener is Aspartame
but other high intensity sweeteners such as Acesulfame, Alatame,
Steviasides, saccharin, cyclamates, etc., may also be employed to
make the agglomerate high intensity sweetener composition of the
invention. The term "active ingredient" is used herein in a broad
sense and means a pharmaceutical such as an antacid, analgesic or
drug; or a flavor, breath sweetener, vitamin, dietary supplement,
or nutrient; or the like and combinations thereof. Active
ingredients include but are not limited to food acids; insoluble
metal and mineral hydroxides, carbonates, oxides, polycarbophils
and salts thereof; adsorbates of active drugs on a magnesium
trisilicate base and on a magnesium aluminum silicate base.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0026] The invention is broadly applicable to making a wide variety
of food and pharmaceutical products including particulate blends
and chewable tablets including but not limited to, sugar free iced
tea mixes, and sugar free antacid tablets, cough medicine tablets,
sore throat tablets, breath freshener tablets, vitamin tablets,
calcium tablets, dietary supplement and nutrient tablets, laxative
tablets, cold tablets, analgesic tablets, anti-diarrhea tablets,
reducing tablets, pain reliever tablets, sleeping tablets, and many
prescription and non-prescription drug and pharmaceutical
tablets.
[0027] Mannitol is the preferred alcohol sugar and the following
will be directed to mannitol for convenience. Other alcohol sugars
include sorbitol and xylitol.
[0028] Agglomerates according to the invention are preferably
formed by a fluidized bed/agglomeration process in which the
particles to be agglomerated are maintained in a gaseous suspension
and a binder in a fine spray is applied to the suspended particles
to cause them to adhere together and build into agglomerated
particles having the open pore, large surface area structure
described herein. The suspended alcohol sugar particles from which
the agglomerates are made preferably pass 50 mesh, while the high
intensity sweetener and ingredients are typically fine powders, for
example, passing 300 mesh.
[0029] The binder may be used alone in solution and/or with the
high intensity sweetener and/or active ingredient. Preferably, the
binder is used to make a binder solution and the alcohol sugar and
high intensity sweetener make up the fluidized bed. The active
ingredient in the final formulation is preferably added by blending
with the agglomerate. The binder is typically applied in a
mist-like or atomized spray having a droplet size of preferably
from about 20 microns to about 100 microns in diameter. The spray
is preferably applied intermittently and the bed particles are
dried between sprayings while they are continuously maintained
suspended and in a fluidized state. Intermittent spray and drying
continues until the required amount of binder solution has been
sprayed into the bed. The moisture content of the bed is thereafter
reduced preferably directly to the final desired moisture content
or the equilibrium moisture content, and the agglomerated particles
are removed from the bed and sized.
[0030] A spray granulator suitable for making agglomerates of the
invention is a Freund Model FL80 pilot-production Flow-Coater. A
schematic diagram of the Freund Model FL80 Flow-Coater is depicted
in FIGS. 1 and 2 of U.S. Pat. No. 4,684,534, supra.
[0031] It is preferred that air be used as the gas for atomizing
the binder solution ("atomizing air"), as the gas for controlling
the pattern of the spray ("spray pattern air"), and as the gas for
suspending and fluidizing the particles in the body of the
fluidized flow coater. Other suitable gases may likewise be
employed.
[0032] The air pressure of the atomizing air and pattern air and
the pumping rate of the liquid binder solution are set and
controlled in accordance with the particular agglomerate being
produced as is well-known in the art. Also controlled are the
quantity of fluidizing air being drawn to fluidize the bed
particles, and the heat exchangers to set the temperature of the
air introduced into the flow coater.
[0033] For the materials disclosed herein and similar materials,
the atomizing air pressure and the pattern air pressure is
typically in the general range of about 1.5 atm to about 6 atm, the
atomizing air flow in the general range of about 100 L/hr to about
200 L/hr, the pattern air flow in the general range of about 10
L/hr to about 40 L/hr, and the liquid binder flow rate in the
general range of about 60 ml/min to about 1,200 ml/min. The
following are preferred: atomizing air pressure and pattern air
pressure, 4 atm; atomizing air flow, 170 L/hr: pattern air flow, 20
L/hr; liquid binder flow rate 250 ml/min; air pressure within the
flow coater, 1 atm; fluidizing air temperature about 60-80.degree.
C.
[0034] The different process parameters described above can be set
and individually controlled by visual observation and manual
setting, or by control systems which semi-automatically or
automatically sense and regulate the parameters in accordance with
a given control sequence. Process parameters for a particular
agglomerate can be programmed into or manually set in to such
control system. Computerized control systems can be used, if
desired, and the construction and operation of control systems for
controlling the foregoing process are within the skill of those in
the computer and control system arts.
[0035] Apparatus other than the Freund FL 80 Flow-Coater can be
used to produce agglomerates according to the invention. One such
apparatus commercially available is a Freund Mini-Flow Coater. This
particular apparatus includes a single, centrally-disposed nozzle
which sprays atomized binder solution into a fluidized bed from
above the bed.
[0036] Agglomerates as shown in the examples below, were made in
accordance with the process described above using a Freund Model FL
80 Flow-Coater or a Freund Mini-Flow-Coater. The agglomerates were
made from materials as indicated below. The maltodextrin binder
materials typically have a DE of less than about 20 and preferably
in the range of about 5 to about 12.
[0037] The alcohol sugar particles passed 50 mesh (particle size
less than about 300 microns), and the high intensity sweetener and
water-insoluble active ingredients passed 325 mesh (particle size
less than about 44 microns). Lubricant particles passed 325 mesh
and other materials such as flavors passed 100 mesh. The precise
size of the alcohol sugar particles is not critical, but
agglomerates made from materials having sizes larger than about 50
mesh for the alcohol sugar particles and larger than about 300 mesh
for the active ingredient generally do not typically produce
tablets which liquify and melt in the mouth as quickly and as
completely as those made with smaller particles. Active ingredients
which do not dissolve in the liquid in which a tablet made from the
agglomerate is to liquify, e.g., water or saliva, preferably have a
particle size of less than about 10 microns. A preferred particle
size for such active ingredients is from about 3 microns to about
10 microns.
[0038] Before being compressed into tablets, the agglomerate
particles are sized preferably between -22 mesh to +100 mesh
(between about 150 microns and about 800 microns). The agglomerate
particle size is also not critical and particles in the above range
produce tablets and flowable particulate products having preferred
characteristics.
[0039] Agglomerates made in accordance with the invention have a
honeycomb or zeolite-like structure as described above, in which
there are large amounts of voids and surface area.
[0040] Tablets made in accordance with the invention were found to
be hard and smooth on the outside but rough, granular and soft on
the inside, normally resistant to moisture on the outside and
liquid-reactive on the inside. When masticated, the tablets
liquefied without perceivable grit within about 20 seconds.
[0041] Specific examples of agglomerates and tablets made from the
agglomerates in accordance with the invention follow. Such Examples
are intended to be exemplary and not to be exhaustive or
limiting.
[0042] In all of the examples which include maltodextrin, the
maltodextrin was Maltrin M-100 (-100 mesh).
EXAMPLES
[0043] The following examples will serve to further illustrate the
components and details of preparation for the mannitol based spray
granulated co-agglomerate combinates of this invention.
Example #1
[0044] A bench model Freund Mini Flow-Coater fluid bed agglomerator
product bowl was charged with:
1 Mannitol USP (fine powder) 435.0 g
[0045] The bed was fluidized and pre-heated for a period of 5
minutes.
[0046] An agglomerating pump solution was prepared as follows:
2 Mannitol USP 15.0 g water 135.0 g
[0047] The mannitol water solution was heated to 45.degree. C. and
stirred until clear.
[0048] The preheated bed was energized with inlet air at a
temperature of 70.degree. C. and the pump solution was delivered at
a rate of 3 ml/minute with an atomizing air pressure of 1.0
ATM.
[0049] The pump solution was delivered intermittently in 1 minute
cycles, followed by air purging of the filter, and the cycles were
continued until all of the mannitol solution was delivered. The
product was then dried to a loss on drying (LOD) moisture content
of less than 0.5%. The finished dust-free agglomerated product
dissolved well in water and when mixed with 1.0% by weight
magnesium stearate pressed into satisfactory non-sweet chewable
tablets.
Example #2
[0050] A bench model Freund Mini Flow-Coater fluid bed agglomerator
product bowl was charged with:
3 Mannitol USP 450 g
[0051] The bed was fluidized and preheated for a period of 5
minutes.
[0052] A agglomerating pump solution was prepared as follows:
4 10 DE Maltodextrin 15 g water 135 g
[0053] the 10 DE maltodextrin solution was heated to 35.degree. C.
and stirred until clear.
[0054] The pre-heated bed was energized with inlet air at a
temperature of 70.degree. C. and the pump solution was delivered
intermittently at a rate of 3 ml/min in 1 minute cycles, followed
by air purging of the filter and the cycles were continued until
all of the maltodextrin pump solution was delivered. The product
was dried to a (LOD) moisture content of less than 1%.
[0055] The finished dust-free agglomerated product dissolved well
in water and when mixed with 1% by weight magnesium stearate
pressed into satisfactory non-sweet chewable tablets.
Example #3
[0056] A bench model Freund Mini Flow-Coater fluid bed agglomerator
product bowl was charged with:
5 Mannitol USP 430.5 g Aspartame 4.5 g
[0057] The bed was energized and fluidized for a period of 5
minutes.
[0058] An agglomerating pump solution was prepared as follows:
6 Mannitol 15.0 g water 135.0 g
[0059] The bed was energized with inlet air at a temperature of
70.degree. C. and the pump solution was delivered at a rate of 3
ml/minute with atomizing air pressure at 1 ATM. The pump solution
was delivered intermittently in 1 minute cycles, followed by air
purging of the filter, and the cycles were continued until all of
the mannitol pump solution was delivered. The product was then
dried to a loss on drying (LOD) moisture content of less than
0.5%.
[0060] The finished dust-free agglomerated product dissolved well
in water and when mixed with 1% by weight magnesium stearate
pressed into commercially satisfactory sweet chewable tablets.
Example #4
[0061] A bench model mini flo-coater fluid bed agglomerator product
bowl was charged with
7 Mannitol 430.5 Aspartame 4.5
[0062] The bed was energized to effect fluidization and mixed for a
period of 5 minutes.
[0063] An agglomerating pump solution was prepared as follows:
8 Maltodextrin (10 DE) 15 g water 135 g
[0064] The maltodextrin water solution was heated to 35.degree. C.
and stirred until clear. The system was energized and the fluidized
bed agglomerated as in example 3.
[0065] The finished dust-free agglomerated product dissolved well
in water and when mixed with 1% by weight magnesium stearate
pressed into commercially satisfactory sweet chewable tablets.
Example #5
[0066] A bench model Freund Mini Flow-Coater fluid bed agglomerator
product bowl was charged with:
9 Mannitol 430.5
[0067] The bed was energized and preheated for a period of 5
minutes. An agglomerating pump solution was prepared as
follows:
10 Maltodextrin 10 DE 15.0 g Aspartame 4.5 g water 135.0 g
[0068] The maltodextrin Aspartame solution was heated to 35.degree.
C. and stirred until clear. The system was energized and the
fluidized bed agglomerated as in Example #3.
[0069] The finished dust-free agglomerated product dissolved well
in water and when mixed with 1% by weight magnesium stearate
pressed into commercially satisfactory sweet chewable tablets.
Example #6
[0070] A bench model Freund Mini-Flow-Coater fluid bed agglomerator
product bowl was charged with
11 Mannitol USP 430.5 g
[0071] The bed was fluidized and preheated for a period of 5
minutes.
[0072] An agglomerating pump solution was prepared as follows:
12 Mannitol 15.0 g Aspartame 4.5 g water 135.0 g
[0073] The mannitol Aspartame solution was heated to 35.degree. C.
and stirred until clear. The system was energized and the fluidized
bed agglomerated as in Example #3.
[0074] The finished dust free agglomerated product dissolved well
in water and when mixed with 1% magnesium stearate pressed well
into satisfactory sweet chewable tablets.
Example #7
[0075] A bench model mini flo-coater fluid bed agglomerator product
bowl was charged with pre-mixed and milled:
13 Mannitol 407.70 g Aspartame 4.95 g corn starch 22.50 g
[0076] The bed was fluidized and preheated for a period of 5
minutes.
[0077] An agglomerating pump solution was prepared as follows:
14 Mannitol 13.5 g Sodium chloride 1.35 g water 135.0
[0078] The mannitol, sodium chloride and water were heated to
35.degree. C. and stirred until clear. The system was energized and
the fluidized bed agglomerated as in example 3.
[0079] The finished dust-free agglomerated product was mixed with
1% magnesium stearate, 3.5% anhydrous citric acid, and 3.5% sodium
bicarbonate. The free flowing dust-free tablet base compressed
readily to form sweet, mildly effervescent, rapidly dissolving
chewable tablets. The tablets maintained their level of
effervescence after storage in glass bottles and held at 37.degree.
C .or 45.degree. C. for a period of 30 days.
Example #8
[0080] A Freund model FL-80 product bowl was charged with the
following materials:
15 Mannitol USP 52.48 kg + A premixed and co-milled blend 14.21 kg
of Mannitol 10.00 kg, Aspartame 0.71 kg and corn starch 3.50 kg
[0081] The loaded product bowl was lifted into position and secured
to seal the agglomerating chamber.
[0082] An agglomerating pump solution was prepared as follows:
16 Maltodextrin 10 DE 3.10 kg Sodium chloride 0.21 3% hydrogen
peroxide 0.25 kg water 14.00 kg
[0083] The mix was charged into an agitated holding tank, heated to
85.degree. C. and mixed until clear.
[0084] The following operational parameters for the agglomeration
of the fluidized bed were set into the operational computer prior
to energizing the machine:
17 Inlet air temperature 70.degree. C. Atomizing air pressure 4 ATM
Pump delivery rate 0.425 L/min. pump cycle 1.0 min. Mechanical
Filter Shake 15 sec. # of pump shake cycles 47 Atomizing air to
spray guns 170 L/Hr Pattern air to spray guns 20 L/Hr Bed mixing
time 5 min.
[0085] With the established parameters entered into the electronic
control system of the FL-80, the machines was energized and
fluidization of the bed was effected.
[0086] After each minute of time in the mix cycle, fluidization was
interrupted and the filters were automatically shaken followed by
re-established fluidization. Following the mix cycle, atomized
agglomerating solution was delivered onto the bed for 1 minute.
Fluidization of the bed was interrupted and followed by filter
shaking to return unagglomerated material to the bed. The spray
shake cycles continued until all of the pump atomizing solution
plus the system flush water was delivered to the bed.
[0087] The bed was then dried by fluidization in the 70.degree. C.
inlet air with the same intermittent shaking cycle interval as in
the mixing mode. The final product was removed at a moisture level
of less than 1% LOD as determined via Computrac moisture
analysis.
[0088] The finished dust-free product demonstrated rapid flow rate
and, with 1% by weight magnesium stearate added, ease of
compression into sweet chewable tablets.
Example #9
[0089] A Freund model FL-80 product bowl was charged with the
following materials:
18 Mannitol USP 52.37 kg + A pre-mixed and co-milled 15.32 kg blend
of Mannitol 10 kg, Aspartame 1.82 kg and corn starch 3.5 kg
[0090] The loaded product bowl was lifted into position and secured
to seal the agglomerating chamber.
[0091] An agglomerating pump solution was prepared as follows:
19 Maltodextrin 10 DE 3.10 kg Sodium Chloride 0.21 kg 3% Hydrogen
peroxide 0.25 kg water 14.00 kg
[0092] The materials were charged into a steam jacketed, agitated
holding tank, heated to 85.degree. C. and mixed until clear.
[0093] The agglomeration of the bed was accomplished in the same
manner as in Example #7 and the same results were obtained.
Example #10
[0094] A Freund model FL-80 product bowl was charged with the
following materials:
20 Mannitol USP 49.44 kg + A pre-mixed and co-milled 17.25 kg blend
of Mannitol 10 kg Aspartame 3.75 kg and corn starch 3.5 kg was
added
[0095] The loaded product was lifted into position and secured in
order to seal the agglomerating chamber.
[0096] An agglomerating pump solution was prepared as follows:
21 Maltodextrin 10 DE 3.10 kg Sodium chloride 0.21 kg 3% Hydrogen
peroxide 0.25 kg water 10.00 kg
[0097] The materials were charged into a steam jacketed, agitated,
holding tank, heated to 85.degree. C. and stirred until clear.
[0098] The agglomeration of the bed was accomplished in the same
manner as in Example #7 and the same results were obtained.
[0099] Analysis of Examples #8, #9 and #10 revealed that the lots
were microbiologically acceptable and that each lot contained the
proper validated quantity of Aspartame.
22 Example #8 Sweet Mannitol with 1% Aspartame Example #9 Sweet
Mannitol with 2.5% Aspartame Example #10 Sweet Mannitol with 5%
Aspartame
Example #11
[0100] The following formulation was prepared utilizing "Sweet
Mannitol with 1% Aspartame Agglomerates" (Example #8):
23 1% Sweet mannitol agglomerates 75.0% w/w Coated pseudoephedrine
HCl (19%) 7.9 Coated chlorpheniramine maleate (10%) 1.0 Tastemasker
4.0 Sodium bicarbonate (-80 mesh) 4.0 Citric acid anhydrous (-80
mesh) 4.0 Flavors 2.6 Magnesium stearate 1.1 Silicon dioxide
0.4
[0101] The tablet ingredients were mixed with the agglomerated 1%
sweet mannitol and compressed. The tablet blend had a high rate of
flow and satisfactorily compressed into {fraction (9/16)}" flat
faced beveled edged 1000 mg tablets at a rate of 2000
tablets/minute. Tablets were ejected at a hardness of 4 kP, and had
a friability of less than 0.5%.
[0102] When placed in the mouth and chewed, the tablets were
satisfactorily liquescent (i.e. dissolved/disintegrated and
swallowed within 20 seconds), Following storage at 37.degree. C.
for a period of 1 year, the tablets evidenced satisfactory chemical
and physical stability with respect to liquescense rate,
effervescent rate, active ingredient content, sodium, sodium
bicarbonate content, Aspartame content, taste, active ingredient
content, color, flavor and hardness.
Example #12
[0103] The following formulation was prepared utilizing "Sweet
Mannitol with 1% Aspartame Agglomerates" (Example #8) and "Sweet
Mannitol with 2.5% Aspartame Agglomerates" (Example #9).
24 Sweet mannitol agglomerates 1% 45.748% w/w Sweet mannitol
agglomerates 2.5% 7.000 Coated pseudoephedrine HCl (19%) 7.900
Dextromethorphan HBr Adsorbate (10%) 5.000 Tastemasker 4.000 Citric
acid anhydrous (-80 mesh) 4.000 Sodium bicarbonate 4.000 Flavor
2.600 Magnesium stearate 1.100 Coated Acetaminophen (93%) 17.2
Coated chlorpheniramine maleate (10%) 1.000 Silicon dioxide 0.400
Lake color 0.052
[0104] The tablet ingredients were mixed with the agglomerated
sweet mannitol and compressed. The tablet blend had a high rate of
flow and satisfactorily compressed into {fraction (9/16)} flat
faced beveled edged 1000 mg tablets at a sustained rate of 2000
tablets/minute. The ejected tablets had a hardness of 4 kP and a
friability value of less than 0.5%.
[0105] When placed in the mouth and chewed, the tablets were
satisfactorily liquescent (i.e., dissolved/disintegrated and
swallowed within 20 seconds). Following storage at 37.degree. C.
for a period of one year, the tablets evidenced satisfactory
chemical and physical stability with respect to liquescense rate,
effervescence rate, active ingredient content, sodium bicarbonate
content, Aspartame content, color, flavor and hardness.
Example #13
[0106] The following formulation was prepared utilizing "Sweet
Mannitol with 2.5% Aspartame Agglomerates" (Example #9):
25 Sweet mannitol agglomerates 2.5% 50.7% w/w Coated Acetaminophen
17.2 Coated pseudoephedrine HCl (19%) 7.9 Dextromethorphan HBr
Adsorbate (10%) 5.0 Flavors 5.1 Tastemasker 4.0 Citric acid
anhydrous (-80 mesh) 4.0 Sodium bicarbonate (-80 mesh) 4.0
Magnesium stearate 1.1 Lake color blend 0.6 Silicon dioxide 0.4
[0107] The tablet ingredients were mixed with the Sweet Mannitol
with 2.5% Agglomerates and compressed. The tablet blend had a high
rate of flow and successfully compressed on {fraction (9/16)} flat
faced beveled edged punches at a weight of 1000 mg/tablet at a
sustained rate of 2000 tablets/minute. The ejected tablets had a
hardness of 4 kP and a friability value of less than 0.5%.
[0108] When placed in the mouth and chewed, the tablets were
satisfactorily liquescent (i.e., dissolved/disintegrated and
swallowed within 20 seconds). Following storage at 37.degree. C.
for a period of one year, the tablets evidenced satisfactory
chemical and physical stability with respect to liquescense rate,
effervescent rate, active ingredient content, sodium bicarbonate
content, Aspartame content, color, flavor and hardness.
Example #14
[0109] The following formulation was prepared utilizing "Sweet
Mannitol with 5% Aspartame Agglomerates" (Example #10):
26 Sweet mannitol agglomerates 5.0% 64.5% w/w Coated Acetaminophen
(93%) 18.0 Tastemasker 4.0 Citric acid anhydrous (-80 mesh) 4.0
Sodium bicarbonate (-30 mesh) 4.0 Magnesium Trisilicate 4.0
Magnesium stearate 1.1 Flavors 0.4
[0110] The tablet ingredients were mixed with the Sweet Mannitol
with 5% Aspartame Agglomerates and compressed. The tablet blend had
a high rate of flow and chewable tablets were compressed at a
weight of 1950 mg on 3/4" standard concave punches at a
satisfactory sustained rate of speed. The ejected tablets had a
hardness of 4-5 kP and a friability value of less than 1%.
[0111] When placed in the mouth and chewed, the tablets were
satisfactorily liquescent (i.e., dissolved/disintegrated and
swallowed within 20 seconds). Following storage stability for a
period of 4 months at 37.degree. C., the tablets evidenced
satisfactory stability with respect to liquescense rate,
effervescence rate, active ingredient content, sodium bicarbonate
content, Aspartame content, color, flavor and hardness.
Example #15
[0112] To show the stability of a high intensity sweetener such as
Aspartame in a tablet made using the preferred alcohol sugar
agglomerates of the invention, dextrose mono-hydrate and mannitol
agglomerates were prepared by a fluidized process as described
above and the agglomerates admixed with Aspartame and other
ingredients as indicated below in the Table to form comparative
tablets. Color change is an indicator of chemical degradation of
the Aspartame via a color changing Maillard reaction. The stability
results in months (m) at a specified temperature are also indicated
below in the Table.
27 TABLE Stability 1 m 2 m 4 m 1 m 4 m 2 m Tablet Original
37.degree. C. 37.degree. C. 37.degree. C. 45.degree. C. 45.degree.
C. 60.degree. C. Dextrose Agglomerate White Tan Dark Tan Brown
Brown Brown Black/Brown & Aspartame Mannitol Agglomerate &
Aspartame White White White White White White White Dextrose
Agglomerate White Tan Dark Tan Brown Brown Brown Black/Brown &
Aspartame, Sodium Bicarbonate & Citric Acid Mannitol
Agglomerate & Aspartame, Sodium White White White White White
White White Bicarbonate & Citric Acid
[0113] As an additional test for formulation stability, the tablets
containing both dextrose, citric acid and sodium bicarbonate were
chemically analyzed for sodium bicarbonate levels. This chemical
analysis for sodium bicarbonate evidenced partial degradation
@37.degree. C./4 m and @45.degree. C./2 m. Full degradation (i.e.
none detected) of the sodium bicarbonate was apparent @60.degree.
C./2 wks.
[0114] The tablets containing mannitol, citric acid and sodium
bicarbonate were also chemically analyzed for sodium bicarbonate
levels. This analysis demonstrated no degradation of the sodium
bicarbonate (i.e. no change from original values at all storage
conditions).
[0115] The above tests clearly show the stability of a high
intensity sweetener such as Aspartame in an agglomerate product of
the invention. Active ingredients such as sodium bicarbonate and
citric acid likewise demonstrated stability for the active
ingredients.
[0116] While the present invention has been particularly described,
in conjunction with a specific preferred embodiment, it is evident
that many alternatives, modifications and variations will be
apparent to those skilled in the art in light of the foregoing
description. It is therefore contemplated that the appended claims
will embrace any such alternatives, modifications and variations as
falling within the true scope and spirit of the present
invention.
* * * * *